Ferroptosis, an iron-dependent form of programmed cell death driven by lipid peroxidation and reactive oxygen species (ROS), has emerged as a key mechanism in the progression of intervertebral disc degeneration (IDD). Mitochondria serve a central role in this process by regulating iron metabolism, ROS production and energy homeostasis. In IDD, mitochondrial dysfunction leads to increased lipid ROS levels, decreased glutathione peroxidase 4 (GPX4) activity and impaired antioxidant defenses, contributing to extracellular matrix degradation and nucleus pulposus cell death. The present review summarizes the core molecular mechanisms underlying ferroptosis and highlights the mitochondrial pathways that mediate ferroptosis in IDD. Furthermore, the advances in mitochondria-targeted therapeutic strategies are discussed, including antioxidants, iron chelators, GPX4 activators, mitophagy modulators and nanotechnology-based interventions. These approaches provide promising avenues for preventing ferroptosis-induced disc degeneration and preserving the viability of disc cells. Understanding the interplay between mitochondrial dysfunction and ferroptosis may offer novel insights for the development of precise and effective treatments for IDD.
Hou et al. (Mon,) studied this question.